EP0002765B1 - Dérivés de céphalosporine, leur préparation et compositions pharmaceutiques et leur préparation - Google Patents

Dérivés de céphalosporine, leur préparation et compositions pharmaceutiques et leur préparation Download PDF

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Publication number
EP0002765B1
EP0002765B1 EP78101738A EP78101738A EP0002765B1 EP 0002765 B1 EP0002765 B1 EP 0002765B1 EP 78101738 A EP78101738 A EP 78101738A EP 78101738 A EP78101738 A EP 78101738A EP 0002765 B1 EP0002765 B1 EP 0002765B1
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Prior art keywords
syn
ppm
amino
acetamido
group
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EP78101738A
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German (de)
English (en)
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EP0002765A1 (fr
Inventor
Jürgen Dr. Blumbach
Walter Dr. Dürckheimer
Elmar Dr. Schrinner
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Hoechst AG
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof

Definitions

  • X represents alkyl having 1 to 4 carbon atoms
  • the radicals methyl, ethyl, propyl and butyl, preferably methyl, may be mentioned in particular.
  • X stands for alkoxycarbonylmethyl with 1 to 4 carbon atoms in the alkyl part, methoxycarbonylmethyl and ethoxycarbonylmethyl are particularly suitable.
  • X in the above meaning of carboxymethyl which may also be in the form of its physiologically acceptable salts, alkoxycarbonylmethyl, aminocarbonylmethyl and cyanomethyl can be substituted in the methylene group by alkyl having 1 to 4 carbon atoms, preferably methyl.
  • radicals X are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, aminocarbonylmethyl and cyanomethyl.
  • Preferred radicals for Y are: methyl, bromine, chlorine and fluorine, but chlorine and fluorine are particularly preferred.
  • esters in the meaning of A the tert-butyl ester and trimethylsilyl ester, and also the benzyl, benzhydryl, trichloroethyl, benzoylmethyl, methoxymethyl or p-methoxybenzyl ester may be mentioned as preferred.
  • physiologically acceptable cations A which may be mentioned are an alkali ion, in particular the sodium and potassium ion, an alkaline earth metal, in particular the calcium and magnesium ion and ammonium ion, but preferably a sodium ion, and an optionally substituted alkylated ammonium ion, such as preferably triethylammonium, diethylammonium, Dimethylammonium or morpholinium, benzylammonium, procainium, L-argininium and L-lysinium.
  • Corresponding physiologically acceptable cations are also suitable for the case where X is in the form of a salt of the carboxymethyl group.
  • the hydroximino or alkoximino group in the compounds of the general formulas I, III, IV and V is in the syn form.
  • 2-aminothiazoles of the general formulas I, III, IV and V can each occur in two tautomeric forms which are present side by side in the equilibrium state and can be represented by the following equilibrium equations.
  • Suitable activated derivatives of the carboxylic acids of the general formula 111 are in particular the halides, preferably chlorides and bromides, furthermore the anhydrides and mixed anhydrides, the azides and activated esters, preferably those with p-nitrophenol, 2,4-dinitrophenol, methylene cyanohydrin, N- Hydroxysuccinimide and N-hydroxyphthalimide, particularly preferably with 1-hydroxybenzotriazole and 6-chloro-1-H-hydroxybenzotriazole.
  • Suitable mixed anhydrides are particularly those with lower alkanoic acids, e.g. B. with acetic acid and particularly preferably with substituted acetic acids, such as. B.
  • the mixed anhydrides with carbonic acid half-esters which are obtained, for example, by reacting the carboxylic acids III in which R 1 is not hydrogen with benzyl chloroformate, p-nitrobenzyl ester, isobutyl ester, ethyl ester or allyl ester are also particularly suitable.
  • the activated derivatives can be implemented as isolated substances, but also in situ.
  • the cephem derivatives II are reacted with the carboxylic acid III or an activated derivative thereof in the presence of an inert solvent.
  • Chlorinated hydrocarbons are particularly suitable, such as preferably methylene chloride and chloroform; Ether such as B.
  • cephem compounds II with carboxylic acids III or their activated derivatives can take place in a temperature range from about -50 to about + 80 ° C, preferably between -20 and + 50 ° C, but particularly preferably between - 20 ° C and room temperature.
  • the reaction time depends on the reactants, the temperature and the solvent or solvent mixture and is normally between about 1/4 and about 72 hours.
  • the reaction of activated derivatives of the carboxylic acids of the formula III with cephem compounds of the formula II is preferably carried out in an alkaline medium above pH 7.
  • a base is added to the reaction mixture, such as preferably potassium or sodium carbonate, potassium or sodium bicarbonate, potassium or sodium hydroxide, pyridine or a trialkylamine, such as, for. B. triethylamine, N-methylmorpholine, ethyldiisopropylamine or potassium tert-butoxide.
  • Cephem compounds of the formula 1 can also be obtained by cleaving the radical R 1 , if it is not hydrogen, into compounds of the formula IV and / or converting the radical X ', if it is not X, into X.
  • R i can be eliminated using gentle methods which are generally customary in ⁇ -lactam and peptide chemistry, such as hydrolysis in acids, preferably formic acid or trifluoroacetic acid, or else hydrogenolysis in the presence of noble metal catalysts.
  • special cleavage reagents can also be used, such as optionally substituted thioureas for removing ⁇ -haloacyl groups.
  • the conversion of the group X ', provided it does not have the meaning of X, into X can also be carried out using gentle hydrolytic or hydrogenolytic methods customary in ⁇ -lactam and peptide chemistry, in particular hydrolysis in inorganic and organic acids, such as preferably trifluoroacetic acid or dilute formic acid.
  • esters of formula and IV in which A has the meaning of an easily removable radical, can - if desired - in a literature manner, gently, for.
  • the R 3 group can also be split off from the radical X 'in the meaning of ⁇ CH 2 C0 2 R 3 in an analogous manner.
  • the Schiff base can also be cleaved by reaction with hydrazine or phenylhydrazine, preferably with Girard reagent or 2,4-dinitrophenylhydrazine.
  • oxidizing agent such as B. proven peroxides, hydroperoxides, peracids, hydrogen peroxide and their mixtures with inorganic and organic, oxidation-resistant acids such as phosphoric acid, formic acid, acetic acid, trifluoroacetic acid.
  • the peracids can also be generated in situ by mixing with hydrogen peroxide.
  • 3-chloroperbenzoic acid has proven particularly useful. It is advantageously used directly.
  • Suitable solvents for the oxidation are all solvents which are stable under the reaction conditions, such as, for. B. dioxane, tetrahydrofuran, chloroform, methylene chloride, acetic acid, formic acid, trifluoroacetic acid, benzene, tetramethylurea, dimethylformamide or dimethylacetamide.
  • the amount of the oxidizing agent is at least 2 oxidation equivalents (corresponding to one active oxygen atom). However, a small excess can also be introduced into the reaction.
  • the reaction temperature is in the range between about -20 and + 80 ° C, but preferably between -20 0 and room temperature.
  • Acyl amino protecting groups on the 7-amino group predominantly provide the 1-sulfoxides with the S configuration.
  • the two configuration isomers can be distinguished and separated chromatographically.
  • NMR spectroscopy can also be used to differentiate the R- and S-sulfoxides (see E. H. Flynn, Cephalosporins and Penicillins, Chemistry and Biology, Academic Press, New York and London, 1972).
  • the carboxylic acids III used for the acylation can be prepared by various methods.
  • compounds of the formula III with Y in the meaning of halogen are obtained by compounds of the formula V in which R 1 and X 'have the abovementioned meanings and R 2 is an alkyl radical having 1-4 C atoms or an aralkyl radical, such as preferably benzyl or phenylethyl, are reacted with a halogenating reagent and optionally the radical R 1 and / or the radical X 'is converted into the form which is most favorable for the following reactions and / or the ester V thus obtained is converted into the carboxylic acid having the general formula III in a manner known per se.
  • Suitable halogenating agents are the elemental halogens, such as preferably bromine and chlorine, trihalogen isocyanuric acids, such as preferably trichloroisocyanuric acid, N-halamides, such as preferably chloramine-T, N-chloroacetamide, N-bromoacetamide, N-haloimides, such as preferably N- Chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, N-bromophthalimide or alkyl hypochlorides such as tert-butyl hypochloride can be used.
  • the reaction is usually carried out in a solvent which does not adversely affect the reaction or even allows it to proceed in the desired direction.
  • a polar, hydroxyl-containing solvent which promotes the formation of positive halogen ions, preferably formic acid, glacial acetic acid, water, alkanols such as, for. B. methanol, ethanol or isopropanol.
  • solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane or dimethylformamide or mixtures thereof with one another or with the abovementioned solvents containing hydroxyl groups can also be recommended.
  • the reaction temperature is not critical, but it is preferably in the range between about ⁇ 20 ° and room temperature.
  • the reaction is expediently carried out with a stoichiometric amount of thiourea in a water-containing solvent, such as. B. ethanol or acetone.
  • a water-containing solvent such as. B. ethanol or acetone.
  • the reaction should be carried out at room temperature and last a maximum of about 2 to 3 hours.
  • thiourea it is expedient to react with a stoichiometric amount of thiourea in a water-containing solvent, such as acetone or ethanol, at room temperature for a maximum of about 2 to 3 hours.
  • a water-containing solvent such as acetone or ethanol
  • the starting compounds of the formula V are known from the literature or can be prepared by processes known from the literature.
  • radical R 1 in the general formulas 111 and V represents an easily removable group which is known from peptide chemistry as an amino protective group, it can be introduced into the amino group in the manner known from peptide chemistry for amino protective groups.
  • R 1 represents the trityl group, for example, it can be introduced with triphenylchloromethane, the reaction advantageously being carried out in an organic solvent, for example halogenated hydrocarbons, in the presence of bases, such as preferably triethylamine.
  • the compounds of the formula I obtained according to the invention show remarkably good antibacterial activities against both gram-positive and gram-negative bacterial germs, which are considerably higher than those of the compounds which are considered to be the closest prior art (FR-A-2 294 690).
  • the new compounds are also unexpectedly effective against bacteria which form penicillinase and cephalosporinase. Since they also have favorable toxicological and pharmacological properties, they are valuable chemotherapeutic agents.
  • the invention thus also relates to pharmaceutical preparations for the treatment of microbial infections which are characterized by a content of one or more of the compounds according to the invention.
  • the products according to the invention can also be used in combination with other active ingredients, for example from the series of penicillins, cephalosporins or aminoglycosides.
  • the compounds of the formula can be administered orally, intramuscularly or intravenously.
  • Medicinal products which contain one or more compounds of the general formula I as an active ingredient can be prepared by the compounds of the general formula I with one or more pharmacologically acceptable carriers or diluents, such as.
  • pharmacologically acceptable carriers or diluents such as.
  • B. fillers, emulsifiers, lubricants, flavoring agents, colorants or buffer substances are mixed and brought into a suitable pharmaceutical preparation, such as tablets, coated tablets, capsules, or a solution or suspension suitable for parenteral administration.
  • suitable pharmaceutical preparation such as tablets, coated tablets, capsules, or a solution or suspension suitable for parenteral administration.
  • carriers or diluents which may be mentioned are tragacanth, milk sugar, talc, agar, polyglycols, ethanol and water. Suspensions or solutions in water are preferred for parenteral administration. It is also possible to apply the active substances as such in a suitable form without a carrier or diluent, for example in capsules.
  • Suitable doses of the compounds of general formula I are about 0.4 to 20 g / day, preferably 0.5 to 4 g / day for an adult of about 60 kg body weight.
  • Single or generally multiple doses can be administered, the single dose containing the active ingredient in an amount of about 50 to 1000 mg, preferably 100 to 500 mg.
  • the product was used without further purification.
  • stage 5 The oil obtained in stage 5 was dissolved in 240 ml of ethanol and mixed with 10 ml of 10N NaOH. After stirring for five hours at room temperature, the mixture was filtered.
  • stage 7 The product obtained in stage 7 was dissolved in 30 ml of CH 2 Cl 2 , cooled under N 2 in an ice bath and mixed with 2.35 g of dicyclohexylcarbodiimide. The mixture was stirred at 0 ° for 1/2 h and at room temperature for 1 h, filtered off from the dicyclohexylurea formed, cooled to 20 ° and with a solution of 2.72 g of 7-aminocephalosporanic acid and 3.3 ml of triethylamine in 40 ml of CH 2 Cl 2 transferred. The mixture was stirred at room temperature for 21 ⁇ 2 hours and then adjusted to pH 2.75 with 1N HCl.
  • the pH was adjusted to 8.0 with saturated NaHCO 3 solution, the mixture was extracted with ethyl acetate, covered with 50 ml of ethyl acetate and brought to pH 2.0 with 2N HCl.
  • the aqueous solution was extracted five times with ethyl acetate, the combined ethyl acetate extracts were dried over Na 2 SO 4 and concentrated on a rotary evaporator.
  • the resulting oil is mixed with 20 ml of ether and stirred for 1 hour, during which it solidifies.
  • the precipitate is suctioned off.
  • the crystals were processed immediately because they decomposed very quickly.
  • the product was immediately processed further due to its fragility.
  • step 4 2.9 g of the product shown in step 4 were mixed with 50 mg of a 1: 1 mixture of ethanol and tetrahydrofuran with 400 mg of thiourea and stirred at room temperature for 15 hours. It is evaporated to dryness in vacuo and taken up in 20 ml of water.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (4)

1. Composés de formule générale 1:
Figure imgb0023
dans laquelle:
n est 0 ou 1 et X représente l'hydrogène, un radical alkyle ayant de 1 à 4 atomes de carbone, un radical carboxyméthyle, alcoxycarbonylméthyle ayant de 1 à 4 atomes de carbone dans le groupe alcoxy, aminocarbonylméthyle ou cyanométhyle, les groupes carboxyméthyle, alcoxycarbonylméthyle, aminocarbonylméthyle et cyanométhyle pouvant également être encore substitués sur leur groupe méthylène par un groupe alkyle ayant de 1 à 4 atomes de carbone, Y représente un radical méthyle ou un halogène, A représente l'hydrogéne, un reste ester facilement séparable ou un cation physiologiquement acceptable et le groupe = N―OX est sous la forme syn.
2. Procédé de préparation de composés de formule générale I selon la revendication 1, caractérisé en ce qu'on fait réagir des lactames de formule générale ll:
Figure imgb0024
dans laquelle n et A ont les significations indiquées cidessus, avec un acide carboxylique de formule générale III:
Figure imgb0025
ou avec un dérivé activé de cet acide, où Y a la signification ci-dessus, R1 représente l'hydrogène ou un groupe amino-protecteur connu dans la chimie des peptides et X' représente X, un groupe facilement séparable ou un groupe de formule:
Figure imgb0026
où R3 représente un reste séparable dans des conditions modérées,
pour obtenir un composé de formule générale IV:
Figure imgb0027
dans laquelle R1, X', Y et A ont les significations indiquées ci-dessus, et éventuellement on oxyde le produit ainsi obtenu sur le soufre du noyau céphème et/ou on sépare un reste R1 représentant un groupe protecteur et/ou on transforme le groupe X' en le groupe X, dans la mesure où X' n'a pas la signification de X.
3. Compositions pharmaceutiques, caractérisées en ce qu'elles contiennent des composés de formule générale I selon la revendication 1.
4. Procédé pour la préparation de compositions pharmaceutiques, caractérisé en ce qu'on met sous une forme d'administration appropriée un composé de formule générale l selon la revendication 1, éventuellement associé avec des véhicules ou des diluants pharmaceutiques usuels.
EP78101738A 1977-12-24 1978-12-16 Dérivés de céphalosporine, leur préparation et compositions pharmaceutiques et leur préparation Expired EP0002765B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19772758001 DE2758001A1 (de) 1977-12-24 1977-12-24 Cephalosporinderivate und verfahren zu ihrer herstellung
DE2758001 1977-12-24

Publications (2)

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EP0002765A1 EP0002765A1 (fr) 1979-07-11
EP0002765B1 true EP0002765B1 (fr) 1981-09-02

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US (1) US4293550A (fr)
EP (1) EP0002765B1 (fr)
JP (1) JPS5495592A (fr)
AT (1) AT365599B (fr)
AU (1) AU534258B2 (fr)
CA (1) CA1109461A (fr)
DE (2) DE2758001A1 (fr)
DK (1) DK578978A (fr)
EG (1) EG13762A (fr)
ES (1) ES476109A1 (fr)
FI (1) FI66007C (fr)
GR (1) GR65234B (fr)
HU (1) HU184140B (fr)
IE (1) IE48147B1 (fr)
IL (1) IL56284A (fr)
NO (1) NO784366L (fr)
NZ (1) NZ189266A (fr)
PH (1) PH15925A (fr)
PT (1) PT68964A (fr)
ZA (1) ZA787209B (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4703046A (en) * 1978-09-08 1987-10-27 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds and processes for preparation thereof
JPS5657790A (en) * 1979-10-02 1981-05-20 Glaxo Group Ltd Cephalosporin antibiotic
US4409214A (en) * 1979-11-19 1983-10-11 Fujisawa Pharmaceutical, Co., Ltd. 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
DE3006888A1 (de) * 1980-02-23 1981-09-10 Hoechst Ag, 6000 Frankfurt Cephalosporinderivate und verfahren zu ihrer herstellung
EP0055465B1 (fr) 1980-12-31 1989-08-23 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'acide 7-acylamino-céphalosporanique et procédés pour leur préparation
JPS57131794A (en) * 1980-12-31 1982-08-14 Fujisawa Pharmaceut Co Ltd Novel cephem compound or salt thereof, preparation of the same and preventing agent and remedy for microbism containing the same as active constituent
US4427677A (en) * 1980-12-31 1984-01-24 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4618606A (en) * 1982-11-17 1986-10-21 Toyama Chemical Co., Ltd. Antibiotic 7-(thiazolyl)-3-(pyrazinylmethyl) or (pyridazinylmethyl) cephalosporins
EP1059293A1 (fr) * 1995-10-12 2000-12-13 Microcide Pharmaceuticals, Inc. Dérivés d'amino-chlorothiazole
IT1295935B1 (it) * 1997-10-30 1999-05-28 Acs Dobfar Spa Derivati aminotiazolici utili nella preparazione di antibiotici b -lattamici
TWI335332B (en) * 2001-10-12 2011-01-01 Theravance Inc Cross-linked vancomycin-cephalosporin antibiotics
CN102015591B (zh) 2008-03-04 2014-01-29 艾尼纳制药公司 制备与5-ht2c激动剂(r)-8-氯-1-甲基-2，3，4，5-四氢-1h-3-苯并氮杂卓相关的中间体的方法
WO2011153206A1 (fr) 2010-06-02 2011-12-08 Arena Pharmaceuticals, Inc. Procédés pour la préparation d'agonistes du récepteur 5-ht2c
KR20140091458A (ko) 2010-09-01 2014-07-21 아레나 파마슈티칼스, 인크. 신장 손상을 갖는 개체에 대한 로카세린의 투여
CN103189359A (zh) 2010-09-01 2013-07-03 艾尼纳制药公司 5-ht2c激动剂的光学活性酸盐
AU2011296003B2 (en) 2010-09-01 2015-11-12 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonist useful for weight management
KR20130101524A (ko) 2010-09-01 2013-09-13 아레나 파마슈티칼스, 인크. 5-ｈｔ2ｃ 아고니스트의 비-흡습성 염
CA2886875A1 (fr) 2012-10-09 2014-04-17 Arena Pharmaceuticals, Inc. Procede de gestion du poids

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5168589A (fr) * 1974-12-06 1976-06-14 Shionogi Seiyaku Kk
DK154939C (da) * 1974-12-19 1989-06-12 Takeda Chemical Industries Ltd Analogifremgangsmaade til fremstilling af thiazolylacetamido-cephemforbindelser eller farmaceutisk acceptable salte eller estere deraf
GB1536281A (en) * 1975-06-09 1978-12-20 Takeda Chemical Industries Ltd Cephem compounds
DE2760123C2 (de) * 1976-01-23 1986-04-30 Roussel-Uclaf, Paris 7-Aminothiazolyl-syn-oxyiminoacetamidocephalosporansäuren, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen

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ZA787209B (en) 1979-12-27
IL56284A (en) 1983-03-31
AU4284878A (en) 1979-06-28
DK578978A (da) 1979-06-25
JPS5495592A (en) 1979-07-28
PH15925A (en) 1983-04-26
FI66007C (fi) 1984-08-10
GR65234B (en) 1980-07-30
IE782546L (en) 1979-06-24
CA1109461A (fr) 1981-09-22
IL56284A0 (en) 1979-03-12
NO784366L (no) 1979-06-26
AU534258B2 (en) 1984-01-12
JPH0132226B2 (fr) 1989-06-29
AT365599B (de) 1982-01-25
US4293550A (en) 1981-10-06
PT68964A (de) 1979-01-01
EG13762A (en) 1982-09-30
DE2861043D1 (en) 1981-11-26
FI783960A (fi) 1979-06-25
FI66007B (fi) 1984-04-30
DE2758001A1 (de) 1979-07-12
IE48147B1 (en) 1984-10-17
EP0002765A1 (fr) 1979-07-11
ATA924178A (de) 1981-06-15
HU184140B (en) 1984-07-30
ES476109A1 (es) 1979-10-16
NZ189266A (en) 1981-12-15

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